The present invention is directed to a method of treating an individual suffering from benign prostate hyperplasmia and prostate cancer.
The prostate gland produces several components of semen in blood and several regulatory peptides. The prostate gland comprises stroma and epithelium cells, the latter group consisting of columnar secretory cells and basal non-secretory cells. The proliferation of these basal cells, as well as stroma cells gives rise to benign prostatic hyperplasmia (BPH) which is one common prostate disease. BPH is a progressive condition which is characterized by the nodular enlargement of the prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, noncuria, poor urine stream, and hesitation or delay in starting the urine flow. Consequences of BPH can include hypertrophy of bladder smooth muscle, decompensated bladder, and increased incidence of urinary tract infection. The development of BPH is considered to be an escapable phenomenon for the aging male population. BPH is observed in approximately 70% of males over the age of 70. Currently in the United States, the method of choice for treating BPH is surgery, e.g., transurethral recession of the prostate. There is no adequate therapeutic drug treatment for BPH.
Another common prostate disease is prostatic adenocarcinoma (CaP) or androgen independent prostate cancer, which involves malignant transformation of epithelial cells in the peripheral region of the prostate gland. Androgen independent prostate cancer is presently the most common cancer in men in the United States with 38,000 deaths anticipated for the USA in 1994, and is a significant condition worldwide. Approximately 50% of patients are presented with metastatic disease. However, the only existing treatment for metastatic disease is hormonal therapy, which is not curative. Thus, the metastatic disease is typically fatal.
Hormonal therapy consisting of different approaches to blocking the action of androgen on the prostate tumor is effective in controlling only the growth of tumor cells that depend on androgen for growth (hormone-dependent tumor). Unfortunately, hormone-dependent tumor inevitably progresses to more advanced hormone-independent tumor, which cannot be controlled by current treatment. Difficulties in treating prostate cancer arise from a variety of reasons. Although such androgen ablation is a standard therapy for metastatic prostate cancer it is rarely entirely successful because in most individuals the cancer is heterogeneous comprising both androgen dependent and androgen independent cancer cells. Thus, the therapy does not eliminate the androgen independent cells.
Chemotherapy, which has been used to treat a number of other cancers, has not proven successful. This is because the vast majority of these androgen independent cells are not actively proliferating and standard chemotherapeutic agents work by selectively killing actively proliferating cells.
Radiation therapy, which also is selective for rapidly proliferating cells, has also not proven effective. Surgery has also not proven an effective means for treating advanced disease states. Accordingly, it would be desirable to have new methods for stimulating the death of these slow proliferating cancer cells. It would be particularly desirable to have a new means of treating individuals suffering from prostate cancer, particularly androgen independent cancer.
.beta.-lapachone (3,4dihydro-s,3-dimethyl-2H-naphthol[1,3-b] pyran-5,6-clone) is a simple plant product with a chemical structure different from currently used anti-cancer drugs. It is obtained by sulfuric acid treatment of the naturally occurring lapachol, which is readily isolated from Tabebuia avellanedae growing mainly in Brazil, or is easily synthesized from lomatiol, isolated from seeds of lomatia growing in Australia (Hooker, S., et. al., J. Am. Chem. Soc., 58:1181-1190 (1936); Goncalves de Lima, O, et al., Rev. Inst. Antibiot. Univ. Recife. 4:3-17 (1962)).
.beta.-lapachone has been shown to have a variety of pharmacological effects. .beta.-lapachone is a topoisomerase I inhibitor but acts by a different mechanism than camptothecin. Numerous .beta.-lapachone derivatives have been synthesized and tested as anti-viral and anti-parasitic agent (Goncalves, A. M., et al., Mol. Biochem. Perasitology, 1:167-176 (1980); Schaffner-Sabba, K., et al., J. Med. Chem., 27:990-994 (1984); Li, C., et al., Proc. Natl. Acad. Sci. USA, 90:187-1842 (1993)). .beta.-lapachone and its derivatives, e.g. 3-allyl-.beta.-lapachone, show anti-trypanosomal effects (Goncalves, A. M., et al., supra), the mechanism of which is unclear. It significantly prolongs the survival of mice infected with Rauscher leukemia virus, probably through inhibition of reverse transcriptase (Schaffner-Sabba, K., et al., supra; Schuerch, A. R., et al., J. Biochem., 84:197-205 (1978)). We taught that .beta.-lapachone also inhibits gene expression directed by the long terminal repeat (LTR) of the human immunodeficiency virus type 1, and viral replication (Li, C., et al., supra). .beta.-lapachone has also been shown to be a DNA repair inhibitor which sensitizes cells to DNA damaging agents (Boorstein, R. J., et al., Biochem. Biophys. Res. Commun., 118:828-834, (1984); Boothman, D. A., et al., J. Cancer Res., 49:605-612 (1989)). .beta.-lapachone is well tolerated in dogs, rats, mice, and chickens. The maximum tolerated dose, when given p.o daily for one month, is 200 mg/kg in rats, and 100 mg/kg in dogs. Higher doses cause gastric ulceration and loss of erythrocytes, but not signs of bone marrow suppression (Ciba-Geigy, personal communication). The previous experience with this compound in humans has been limited.